Treatment of obesity by sub-diaphragmatic nerve stimulation

ABSTRACT

A method and apparatus for treating obese or other patients with compulsive overeating disorder includes unilaterally or bilaterally stimulating one or both of the left and right branches of a patient&#39;s vagus nerve directly or indirectly with an electrical pulse signal generated by an implantable neurostimulator with at least one operatively coupled nerve electrode to apply the pulse signal to the selected nerve branch at a location below the patient&#39;s diaphragm. The implantable neurostimulator is programmable to enable physician programming of electrical and timing parameters of the pulse signal, to induce weight loss of the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 09/753,758,filed Jan. 2, 2001, assigned to the same assignee as the presentapplication, now U.S. Pat. No. 6,609,025, issued Aug. 19, 2003.

BACKGROUND OF THE INVENTION

The present invention relates generally to methods and apparatus fortreating eating disorders by application of modulating electricalsignals to a selected cranial nerve, nerve branch or nerve bundle, andmore particularly to techniques for treating patients with overeatingdisorders, especially obese patients, by application of such signalsunilaterally or bilaterally to the patient's vagus nerve with one ormore neurostimulating devices.

Increasing prevalence of obesity is one of the most serious andwidespread health problems facing the world community. It is estimatedthat, currently, about 6% of the total population of the United Statesis morbidly obese and a much larger percentage is either obese orsignificantly overweight. Morbid obesity is defined as having a bodymass index of more than forty, or, as is more commonly understood, beingmore than one hundred pounds overweight for a person of average height.Aside from what may be an epidemic of obesity, it is believed by manyhealth experts that obesity is one of the first two leading causes ofpreventable deaths in the United States, either ahead of or just behindcigarette smoking. or not that is an accurate assessment, studies haveindicated that morbid obesity dramatically increases health care costs.It is a major cause of adult onset diabetes in the United States, up toapproximately eighty percent of the cases. It may be a leading factor inas many as ninety percent of sleep apnea cases. Obesity is also asubstantial risk factor for coronary artery disease, stroke, chronicvenous abnormalities, numerous orthopedic problems and esophageal refluxdisease. Researchers have documented a link between obesity, infertilityand miscarriages, as well as post menopausal breast cancer.

The classical treatment option for obese people combines nutritionalcounseling with exercise and education, but has demonstrated relativelylittle long term success. Liquid diets and pharmaceutical agents canbring about acute, but not lasting weight loss. Surgical procedures foreither gastric restriction or malabsorption in cases of severe obesityhave shown the greatest success long-term, but are major surgery thatcan lead to emotional problems, and have their share of failures (e.g.,Kriwanek, “Therapeutic failures after gastric bypass operations formorbid obesity,” Langenbecks Archiv. Fur Chirurgie, 38(2): 70-74, 1995).

U.S. Pat. No. 5,263,480 to J. Wemicke et al., assigned to the sameassignee as the present application, discloses treatment for eatingdisorders including obesity and compulsive overeating disorder byselectively applying modulating electrical signals to the patient'svagus nerve, preferably using an implanted neurostimulator. Modulatingsignals may be used to stimulate vagal activity to increase the flow ofneural impulses up the nerve, or to inhibit vagal activity to blockneural impulses from moving up the nerve, toward the brain, forproducing excitatory or inhibitory neurotransmitter release.

Both of these cases of modulating the electrical activity of the vagusnerve have been termed vagus nerve stimulation, or VNS. The '480 patenttheorized that VNS could be used for appetite suppression by causing thepatient to experience satiety, a sensation of “fullness” of the stomachwhich would result in decreased food consumption and consequent weightreduction. For example, the stimulus generator of the neurostimulator isimplanted in a convenient location in the patient's body, attached to anelectrical lead having a nerve electrode implanted on the vagus nerve orbranch thereof in the esophageal region slightly above the stomach. Ifthe patient's food consumption over a given period exceeded apredetermined threshold level, detected and measured for example bysensing electrodes implanted at or near the esophagus, the stimulusgenerator is triggered to apply VNS and thereby induce satiety.Alternatively, VNS is applied periodically during the patient's normalwaking hours except in periods of prescribed mealtimes, or is applied asa result of patient intervention by manual activation of the stimulusgenerator using external magnet control. Patient intervention assumes apatient with an earnest desire to control his or her eating behavior,but normally lacking will power to control the compulsive behaviorwithout the support of VNS.

Like most of the pairs of cranial nerves, the tenth cranial nerve, thevagus, originates from the brain stem. It passes through foramina of theskull to parts of the head, neck and trunk. The vagus is a mixed nerve,with both sensory and motor fibers, the sensory fibers being primary andattached to neuron cell bodies located outside the brain in gangliagroups, and the motor fibers attached to neuron cell bodies locatedwithin the gray matter of the brain. The vagus, as a cranial nerve, ispart of the peripheral nervous system or PNS whose nerves branch outfrom the central nervous system (CNS) to connect the CNS to other bodyparts. Somatic fibers of the cranial nerves are involved in consciousactivities and connect the CNS to the skin and skeletal muscles, whileautonomic fibers of these nerves are involved in unconscious activitiesand connect the CNS to the visceral organs such as the heart, lungs,stomach, liver, pancreas, spleen, and intestines.

The motor fibers of the vagus nerve transmit impulses to the musclesassociated with speech and swallowing, the heart, and smooth muscles ofthe visceral organs of the thorax and abdomen. In contrast, its sensoryfibers transmit impulses from the pharynx, larynx, esophagus andvisceral organs of the thorax and abdomen. The vagus is split into leftand right branches, or left and right vagi, which run respectivelythrough the left and right sides of the neck and trunk. It is the axialportion of the body, which includes the head, neck and trunk with whichwe are primarily concerned in respect of the present invention. Theventral cavity of the axial portion contains visceral organs andincludes the thoracic cavity and the abdominopelvic cavity, which areseparated by the diaphragm, a broad thin muscle. Visceral organs in thethoracic cavity include the right and left lungs, the heart, theesophagus, the trachea and the thymus gland. Below the diaphragm, in theabdominopelvic cavity and specifically the upper abdominal portion orabdominal portion, the visceral organs therein include the stomach,liver, spleen, gall bladder, and majority of the small and largeintestines.

The vagus nerve is the dominant nerve of the gastrointestinal (GI)tract, the right and left branches or nerve afferents of the vagusconnecting the GI tract to the brain. After leaving the spinal cord, thevagal afferents transport information regarding that tract to the brain.In the lower part of the chest, the left vagus rotates, becomes theanterior vagus, and innervates the stomach. The right vagus rotates tobecome the posterior vagus, which branches into the celiac division andinnervates the duodenum and proximal intestinal tract.

The exact mechanisms leading an individual to satiety are not fullyknown, but a substantial amount of information has been accumulated.Satiety signals include the stretch of mechanoreceptors, and thestimulation of certain chemosensors (e.g., “A Protective Role for VagalAfferents: An Hypothesis,” Neuroanatomy and Physiology of AbdominalVagal Afferents, Chapter 12, CRC Press, 1992). These signals aretransported to the brain by the nervous system or endocrine factors suchas gut peptides (e.g., “External Sensory Events and the Control of theGastrointestinal Tract: An Introduction” id. at Chapter 5). It has beendemonstrated that direct infusion of maltose and oleic acid into theduodenum of rats leads to a reduction in food intake, and that theresponse is ablated by vagotomy or injection of capsaicin, whichdestroys vagal afferents. Introduction of systemic cholecystokinin alsoreduces intake in rats, and is ablated by destruction of vagalafferents.

While the vagus is often considered to be a motor nerve which alsocarries secretory signals, 80% of the nerve is sensory consisting ofafferent fibers (e.g., Grundy et al., “Sensory afferents from thegastrointestinal tract,” Handbook of Physiology, Sec. 6, S. G., Ed.,American Physiology Society, Bethesda, Md., 1989, Chapter 10).

The aforementioned '396 application discloses a method of treatingpatients for obesity by bilateral stimulation of the patient's vagusnerve (i.e., bilateral VNS) in which a stimulating electrical signal isapplied to one or both branches of the vagus. The parameters of thesignal are predetermined to induce weight loss of the patient. Thesignal is preferably a pulse signal applied at a set duty cycle (i.e.,its on and off times) intermittently to both vagi. In any event, VNS isapplied at a supra-diaphragmatic position (i.e., above the diaphragm) inthe ventral cavity. The electrical pulse stimuli are set at a currentmagnitude below the retching level of the patient (e.g., not exceedingabout 6 milliamperes (mA), to avoid patient nausea) in alternatingperiods of continuous application and no application. Pulse width is setat or below 500 microseconds (μs), and pulse repetition frequency atabout 20-30 Hz. The on/off duty cycle (i.e., first period/second periodof the alternating periods) is programmed to a ratio of about 1:1.8. Theneurostimulator, which may be a single device or a pair of devices, isimplanted and electrically coupled to lead(s) having nerve electrodesimplanted on the right and left branches of the vagus.

SUMMARY OF THE INVENTION

According to the present invention, a method of treating patients forobesity comprises unilateral or bilateral stimulation of the left andright vagi at a sub-diaphragmatic position (i.e., below the diaphragm)in the ventral cavity, rather than at a supra-diaphragmatic position astaught by the '396 application. The stimulating electrical signal ispreferably applied to the vagus two to three inches below the diaphragm,and may be applied either synchronously or asynchronously to both theright and left branches, preferably in the form of a series of pulsesapplied intermittently to both branches according to a predeterminedon/off duty cycle. The intermittent application is preferably chronic,rather than acute. However, continuous application or acute applicationby bilateral stimulation of the right and left vagi or unilateralstimulation of either branch, at the sub-diaphragmatic position, is alsocontemplated.

The sub-diaphragmatic application of VNS may have an enhanced effect ininducing satiety in the patient, being in closer proximity to thestomach itself. Certainly, in the case of neurostimulator deviceimplantation superficially in the abdominal region of the patient, thesub-diaphragmatic application has an advantage of enabling shorter leadsfor the nerve electrode(s). Additionally, application of theneurostimulator may be more easily accomplished with this approach asopposed to a supra-diaphragmatic approach which requires accessing thevagi in the chest cavity.

Acute application of the stimulating electrical signal to the right andleft vagi during a customary mealtime, or from a short time precedingand/or following the mealtime, according to the patient's circadiancycle, may be effective in certain cases. Automatic delivery ofbilateral intermittent stimulation is preferred, but it is alternativelypossible to control application of the stimulating electrical signal tothe right and left vagi by an external commencement signal produced bythe patient's placement of an external magnet, or by anotherpatient-applied signal, in proximity to the location of the implanteddevice.

Preferably, the same stimulating electrical signal is applied to boththe right and left vagi, but as an alternative, a stimulating electricalsignal might be applied to the right vagus which is different from thestimulating electrical signal applied to the left vagus. And althoughtwo separate nerve stimulator generators may be implanted forstimulating the left and right vagi, respectively, as an alternative asingle nerve stimulator generator may be implanted for bilateralstimulation if the same signal is to be applied to both the left andright branches of the vagus nerve, whether, delivered synchronously orasynchronously to the vagi.

As with the method disclosed in the '396 application, the currentmagnitude of the stimulating signal is programmed to be less than about6 mA, and in any case is held below the retching level of the patient asdetermined by the implanting physician at the time the implant procedureis performed, or shortly thereafter. This is important to avoid patientnausea during periods of vagus nerve stimulation. Preferably, the pulsewidth is set to a value not exceeding about 500 μs, the pulse repetitionfrequency is set at about 20-30 Hertz (Hz), the VNS regimen followsalternating periods of stimulation and no stimulation, with the secondperiod about 1.8 times the length of the first period in the alternatingsequence (i.e., the on/off duty cycle is 1:1.8).

The apparatus of the present invention for treating obese patientssuffering from eating disorders includes an implanted neurostimulatorfor simultaneously stimulating left and right branches of the patient'svagus nerve via separate lead/electrodes operatively coupled to theneurostimulator and implanted on the right and left vagi in asub-diaphragmatic position, the stimulation being applied continuouslyduring a first period, alternating with no stimulation during a secondperiod, throughout the prescribed duration of the stimulation regimen.

Accordingly, it is a principal objective of the present invention toprovide methods and apparatus for treating and controlling theovereating disorder, especially in obese patients, by means of bilateralelectrical stimulation of the patient's right and left vagi at asub-diaphragmatic location.

Another aim of the invention is to provide methods of treating andcontrolling compulsive overeating and obesity by bilateral intermittentelectrical pulse stimulation of right and left vagi at asub-diaphragmatic position in the patient.

Alternative techniques include indirect stimulation of the vagus, eitherbilaterally or unilaterally, at a location near one or both branches ofthe nerve or elsewhere, which has the effect of stimulating the vagusnerve as well. This may be accomplished through afferents or efferents,for example.

It is also contemplated that direct or indirect unilateral or bilateralstimulation applied at or by way of a sub-diaphragmatic location of oneor more of the other cranial nerves of suitable sensory, motor or mixedfiber types may be effective in treating compulsive overeating disorder,as an alternative to vagus nerve stimulation.

Some differences may be observed from stimulator to stimulator inmagnitude of current in the pulses of the stimulation signal, and may beattributable to things such as patient impedance, variation of the vagusnerve from right to left or between patients, and variation in contactbetween the vagus and the electrode implanted thereon from implant toimplant.

According to other aspects of treatment by stimulation of the vagus orother suitable cranial nerve in the vicinity of the patient's diaphragm,beneficial weight reduction is aided by increased activity attributableto release of norepinephrine, serotonin or other mechanisms, increasedmetabolism and change in gastric motility. This therapy may also havebeneficial effect in treatment of other disorders such as type IIdiabetes, high blood pressure and orthopedic problems which typicallyco-exist with compulsive overeating disorder and obesity.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and still further aims, objectives, aspects, features andattendant advantages of the present invention will be better understoodfrom a consideration of the following detailed description of apresently contemplated best mode of practicing the invention, byreference to a preferred exemplary method and embodiment thereof, takenin conjunction with the accompanying Figures of drawing, in which:

FIG. 1 is a simplified partial front view of a patient (in phantom)having an implanted neurostimulator for generating the desired signalstimuli which are applied directly and bilaterally at sub-diaphragmaticlocation to the right and left branches of the patient's vagus via animplanted lead/nerve electrode system electrically connected to theneurostimulator;

FIG. 2 is a simplified partial front view of a patient similar to thatof FIG. 1, but in which a pair of implanted neurostimulators is used forgenerating the desired signal stimuli;

FIG. 3 is a simplified partial front view of a patient in which animplanted neurostimulator and associated electrode is used forunilateral stimulation of only one branch of the vagus nerve;

FIG. 4 is a simplified partial front view of a patient in which thesignal stimuli are applied at a portion of the nervous system remotefrom the vagus nerve such as at or near the stomach wall, for indirectstimulation of the vagus nerve; and

FIG. 5 is a simplified partial front view of a patient in which thesignal stimuli are applied remotely from electrical stimulating deviceplaced by an endoscope from an area composing the GI tract.

DESCRIPTION OF THE PRESENTLY CONTEMPLATED BEST MODE

A generally suitable form of neurostimulator for use in the apparatusand method of the present invention is disclosed, for example, in U.S.Pat. No. 5,154,172, assigned to the same assignee as the instantapplication (the device also referred to from time to time herein as aNeuroCybernetic Prosthesis or NCP device (NCP is a trademark ofCyberonics, Inc. of Houston, Tex., the assignee)). Certain parameters ofthe electrical stimuli generated by the neurostimulator areprogrammable, preferably by means of an external programmer (not shown)in a conventional manner for implantable electrical medical devices.

Referring to FIG. 1, the neurostimulator, identified in the drawing byreference number 10 is implanted in a patient 12, preferably in theabdominal region, for example, via a left laparotomy incision. For thepreferred implementation and method of direct bilateral stimulation,lead-electrode pair 15, 16 is also implanted during the procedure, andthe proximal end(s) of the lead(s) electrically connected to theneurostimulator. The lead-electrode may be of a standard bipolar leadnerve electrode type available from Cyberonics, Inc.

According to the preferred method of the invention, the nerve electrodes17, 18 are implanted on the right and left branches 19, 20,respectively, of the patient's vagus nerve at a sub-diaphragmaticlocation. The nerve electrodes are equipped with tethers for maintainingeach electrode in place without undue stress on the coupling of theelectrode onto the nerve itself. Preferably, the sub-diaphragmaticlocation of this coupling is approximately two to three inches below thepatient's diaphragm 22 for each branch 19, 20.

Neurostimulator 10 generates electrical stimuli in the form ofelectrical impulses according to a programmed regimen for bilateralstimulation of the right and left branches of the vagus. During theimplant procedure, the physician checks the current level of the pulsedsignal to ascertain that the current is adjusted to a magnitude at leastslightly below the retching threshold of the patient. Typically, if thislevel is programmed to a value less than approximately 6 mA, the patientdoes not experience retching attributable to VNS although variations maybe observed from patient to patient. In any event, the maximum amplitudeof the current should be adjusted accordingly until an absence ofretching is observed, with a suitable safety margin. The retchingthreshold may change noticeably with time over a course of days afterimplantation, so the level should be checked especially in the first fewdays after implantation to determine whether any adjustment is necessaryto maintain an effective regimen.

The bilateral stimulation regimen of the VNS preferably employs anintermittent pattern of a period in which a repeating series of pulsesis generated for stimulating the nerve, followed by a period in which nopulses are generated. The on/off duty cycle of these alternating periodsof stimulation and no stimulation preferably has a ratio in which theoff time is approximately 1.8 times the length of the on time.Preferably also, the width of each pulse is set to a value not greaterthan about 500 μs, and the pulse repetition frequency is programmed tobe in a range of about 20 to 30 Hz. The electrical and timing parametersof the stimulating signal used for VNS as described herein for thepreferred embodiment will be understood to be merely exemplary and notas constituting limitations on the scope of the invention.

The patient's eating behavior should be allowed to stabilize atapproximately the preoperative level before the VNS regimen is actuallyadministered. Treatment applied in the form of chronic intermittentbilateral nerve stimulation over each twenty-four hour period may beobserved initially to result in no change in eating behavior of thepatient. But after a period of several days of this VNS regimen, adiscernible loss of interest in heavy consumption of food should occur.A typical result would be that mealtime consumption tends to stretchover a considerably longer period of time than that observed for thepatient's preoperative behavior, with smaller quantities of food intakeseparated by longer intervals of no consumption in the course of asingle meal. The VNS treatment should not affect normal behavior inother aspects of the patient's life. A complete suspension of the VNSregimen would result in a relatively rapid return to the previousovereating behavior, ending after resumption of the VNS regimen.Observations appear to indicate that treatment by bilateral stimulationmay be safe and effective in changing eating patterns and behavior inobese human patients, and more generally in human patients sufferingfrom compulsive overeating disorder.

Animal testing using bilateral VNS has tended to demonstrate that slowedeating and apparent lack of enthusiasm in food consumption is centrallymediated and the result of a positive response of inducing a sensationof satiety mimicking that which would occur after consumption of a fullmeal, rather than of a negative response of nausea or sick stomach.

The intermittent aspect of the bilateral stimulation resides in applyingthe stimuli according to a prescribed duty cycle. The pulse signal isprogrammed to have a predetermined on-time in which a train or series ofelectrical pulses of preset parameters is applied to the vagus branches,followed by a predetermined off-time. Nevertheless, continuousapplication of the electrical pulse signal may also be effective intreating compulsive overeating disorder.

Also, as shown in FIG. 2, dual implanted NCP devices 10 a and 10 b maybeused as the pulse generators, one supplying the right vagus and theother the left vagus to provide the bilateral stimulation. At leastslightly different stimulation for each branch may be effective as well.Use of implanted stimulators for performing the method of the inventionis preferred, but treatment may conceivably be administered usingexternal stimulation equipment on an outpatient basis, albeit onlysomewhat less confining than complete hospitalization. Implantation ofone or more neurostimulators, of course, allows the patient to becompletely ambulatory, so that normal daily routine activities includingon the job performance is unaffected.

The desired stimulation of the patient's vagus nerve may also beachieved by performing unilateral sub-diaphragmatic stimulation ofeither the left branch or the right branch of the vagus nerve, as shownin FIG. 3. A single neurostimulator 10 is implanted together with a lead15 and associated nerve electrode 17. The nerve electrode 17 isimplanted on either the right branch 19 or the left branch 20 of thenerve, preferably in a location in a range of from about two to aboutthree inches below the patient's diaphragm 22. The electrical signalstimuli are the same as described above.

In a technique illustrated in FIG. 4, the signal stimuli are applied ata portion of the nervous system remote from the vagus nerve such as ator near the stomach wall 25, for indirect stimulation of the vagus nervein the vicinity of the sub-diaphragmatic location. Here, at least onesignal generator 10 is implanted together with one or more electrodes 17subsequently operatively coupled to the generator via lead 15 forgenerating and applying the electrical signal internally to a portion ofthe patient's nervous system other than the vagus nerve, to provideindirect stimulation of the vagus nerve in the vicinity of the desiredlocation. Alternatively, the electrical signal stimulus may be appliednon-invasively to a portion of the patient's nervous system for indirectstimulation of the vagus nerve at a sub-diaphragmatic location.

In an arrangement shown in FIG. 5, the signal stimuli are appliedremotely from electrical stimulating device 10 placed by an endoscope 27from an area composing the GI tract 30.

It is again noted that the principles of the invention may be applicableto selected cranial nerves other than the vagus, to achieve the desiredresults. It will thus be seen that a variety of different techniques andarrangements may be employed to practice the invention. Accordingly,although a presently contemplated best mode and certain other modes oftreating and controlling overeating disorders to induce weight loss inthe patient through a regimen of cranial nerve, and more specificallyvagus nerve, stimulation either directly or indirectly at asub-diaphragmatic location has been described herein, variations andmodifications may be made within the scope of the present invention. Itis therefore desired that the invention be limited only as required bythe following claims and by the rules and principles of the applicablelaw.

1. A method of treating an obese patient, comprising: surgicallyimplanting in the abdomen of the patient an electrical signal generatorand electrodes operatively coupled thereto for generating and applyingsaid electrical signal internally at a location below the patient'sdiaphragm to indirectly stimulate a selected one of the left branch andthe right branch of the vagus nerve; applying said electrical signalindirectly and unilaterally to said selected one of the left branch andthe right branch of the vagus nerve internally in the abdomen at saidlocation below the patient's diaphragm; and programming electrical andtiming parameters of said electrical signal, to induce weight loss ofthe patient.
 2. The method of claim 1, wherein said electrical signalcomprises a sequence of electrical pulses.
 3. The method of claim 1,wherein the step of applying comprises applying said electrical signalto the selected one of the left branch and the right branch of the vagusnerve at a location in a range of from about two to about three inchesbelow the patient's diaphragm.
 4. The method of claim 1, wherein thestep of applying comprises applying said electrical signalintermittently, in alternating on and off intervals according to apredetermined duty cycle.
 5. The method of claim 1, wherein the step ofapplying includes applying said electrical signal continuously.
 6. Amethod of treating a patient with compulsive eating disorder, saidmethod comprising: applying an electrical signal to the vagus nerve ofthe patient at a sub-diaphragmatic location to induce a signal in thenerve toward the patient's brain, and programming electrical and timingparameters of said electrical signal to control said eating disorder,wherein said applying comprises indirectly and unilaterally stimulatinga selected one of the left branch and the right branch of the vagusnerve in the vicinity of the sub-diaphragmatic location by applying saidelectrical signal internally at said sub-diaphragmatic location which isremoved from said selected left or right branch of the vagus nerve, byway of at least one electrode surgically implanted in the abdomen of thepatient at the sub-diaphragmatic location.
 7. The method of claim 6,wherein said electrical signal comprises a sequence of electricalpulses.
 8. The method of claim 6, wherein the step of applying comprisesapplying said electrical signal to the selected one of the right branchand the left branch of the vagus nerve at said location in a range offrom about two to about three inches below the patient's diaphragm.
 9. Amethod of treating a patient with compulsive eating disorder, saidmethod comprising: surgically implanting at least one pulse generatorwith surgically implanted nerve electrodes coupled thereto into theabdomen of the patient to generate and apply an electrical signal as asequence of electrical impulses indirectly and unilaterally to aselected one of the left branch and the right branch of the vagus nerve;programming electrical and timing parameters of said electrical signalto control said eating disorder, and applying said electrical signalindirectly and unilaterally to said selected one of the left branch andthe right branch of the vagus nerve of the patient at asub-diapbragmatic location, to induce a signal in the nerve toward thepatient's brain to control said eating disorder of the patient.